Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin
Identifieur interne : 005A62 ( Main/Exploration ); précédent : 005A61; suivant : 005A63Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin
Auteurs : Peter Huppke [Allemagne] ; Cornelia Brendel [Allemagne] ; Vera Kalscheuer [Allemagne] ; Georg Christoph Korenke [Allemagne] ; Iris Marquardt [Allemagne] ; Peter Freisinger [Allemagne] ; John Christodoulou [Australie] ; Merle Hillebrand [Allemagne] ; Gaele Pitelet [France] ; Callum Wilson [Nouvelle-Zélande] ; Ursula Gruber-Sedlmayr [Autriche] ; Reinhard Ullmann [Allemagne] ; Stefan Haas [Allemagne] ; Orly Elpeleg [Israël] ; Gudrun Nürnberg [Allemagne] ; Peter Nürnberg [Allemagne] ; Shzeena Dad [Danemark] ; Lisbeth Birk M Ller [Danemark] ; Stephen G. Kaler [États-Unis] ; Jutta G Rtner [Allemagne]Source :
- American journal of human genetics [ 0002-9297 ] ; 2012.
Descripteurs français
- Pascal (Inist)
- Wicri :
English descriptors
- KwdEn :
Abstract
Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.
Affiliations:
- Allemagne, Australie, Autriche, Danemark, France, Israël, Nouvelle-Zélande, États-Unis
- Basse-Saxe, Berlin, District de Cologne, Nouvelle-Galles du Sud, Rhénanie-du-Nord-Westphalie
- Berlin, Cologne, Göttingen, Sydney
- Université de Sydney
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin</title><author><name sortKey="Huppke, Peter" sort="Huppke, Peter" uniqKey="Huppke P" first="Peter" last="Huppke">Peter Huppke</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Brendel, Cornelia" sort="Brendel, Cornelia" uniqKey="Brendel C" first="Cornelia" last="Brendel">Cornelia Brendel</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>3 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Christoph Korenke, Georg" sort="Christoph Korenke, Georg" uniqKey="Christoph Korenke G" first="Georg" last="Christoph Korenke">Georg 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type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><author><name sortKey="Hillebrand, Merle" sort="Hillebrand, Merle" uniqKey="Hillebrand M" first="Merle" last="Hillebrand">Merle Hillebrand</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Pitelet, Gaele" sort="Pitelet, Gaele" uniqKey="Pitelet G" first="Gaele" last="Pitelet">Gaele Pitelet</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Service de Neuropediatrie, CHU Nice</s1><s2>6200 Nice</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>6200 Nice</wicri:noRegion><wicri:noRegion>CHU Nice</wicri:noRegion><wicri:noRegion>6200 Nice</wicri:noRegion></affiliation></author><author><name sortKey="Wilson, Callum" sort="Wilson, Callum" uniqKey="Wilson C" first="Callum" last="Wilson">Callum Wilson</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>National Metabolic Service, Starship Children's Hospital</s1><s2>1142 Auckland</s2><s3>NZL</s3><sZ>10 aut.</sZ></inist:fA14><country>Nouvelle-Zélande</country><wicri:noRegion>1142 Auckland</wicri:noRegion></affiliation></author><author><name sortKey="Gruber Sedlmayr, Ursula" sort="Gruber Sedlmayr, Ursula" uniqKey="Gruber Sedlmayr U" first="Ursula" last="Gruber-Sedlmayr">Ursula Gruber-Sedlmayr</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Pediatrics, Medical University of Graz</s1><s2>8010 Graz</s2><s3>AUT</s3><sZ>11 aut.</sZ></inist:fA14><country>Autriche</country><wicri:noRegion>8010 Graz</wicri:noRegion></affiliation></author><author><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>3 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Haas, Stefan" sort="Haas, Stefan" uniqKey="Haas S" first="Stefan" last="Haas">Stefan Haas</name><affiliation wicri:level="3"><inist:fA14 i1="09"><s1>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>13 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Elpeleg, Orly" sort="Elpeleg, Orly" uniqKey="Elpeleg O" first="Orly" last="Elpeleg">Orly Elpeleg</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Monique and Jacques Roboh Department of Genetic Research, Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center</s1><s2>91050 Jerusalem</s2><s3>ISR</s3><sZ>14 aut.</sZ></inist:fA14><country>Israël</country><wicri:noRegion>91050 Jerusalem</wicri:noRegion></affiliation></author><author><name sortKey="Nurnberg, Gudrun" sort="Nurnberg, Gudrun" uniqKey="Nurnberg G" first="Gudrun" last="Nürnberg">Gudrun Nürnberg</name><affiliation wicri:level="3"><inist:fA14 i1="11"><s1>Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne</s1><s2>50931 Cologne</s2><s3>DEU</s3><sZ>15 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Cologne</settlement></placeName></affiliation></author><author><name sortKey="Nurnberg, Peter" sort="Nurnberg, Peter" uniqKey="Nurnberg P" first="Peter" last="Nürnberg">Peter Nürnberg</name><affiliation wicri:level="3"><inist:fA14 i1="11"><s1>Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne</s1><s2>50931 Cologne</s2><s3>DEU</s3><sZ>15 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Cologne</settlement></placeName></affiliation></author><author><name sortKey="Dad, Shzeena" sort="Dad, Shzeena" uniqKey="Dad S" first="Shzeena" last="Dad">Shzeena Dad</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department for Applied Human Molecular Genetics Kennedy Center</s1><s2>2600 Glostrup</s2><s3>DNK</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Danemark</country><wicri:noRegion>Department for Applied Human Molecular Genetics Kennedy Center</wicri:noRegion></affiliation></author><author><name sortKey="Birk M Ller, Lisbeth" sort="Birk M Ller, Lisbeth" uniqKey="Birk M Ller L" first="Lisbeth" last="Birk M Ller">Lisbeth Birk M Ller</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department for Applied Human Molecular Genetics Kennedy Center</s1><s2>2600 Glostrup</s2><s3>DNK</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Danemark</country><wicri:noRegion>Department for Applied Human Molecular Genetics Kennedy Center</wicri:noRegion></affiliation></author><author><name sortKey="Kaler, Stephen G" sort="Kaler, Stephen G" uniqKey="Kaler S" first="Stephen G." last="Kaler">Stephen G. Kaler</name><affiliation wicri:level="1"><inist:fA14 i1="13"><s1>Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health</s1><s2>Bethesda, MD 20814</s2><s3>USA</s3><sZ>19 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Bethesda, MD 20814</wicri:noRegion></affiliation></author><author><name sortKey="G Rtner, Jutta" sort="G Rtner, Jutta" uniqKey="G Rtner J" first="Jutta" last="G Rtner">Jutta G Rtner</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">12-0206474</idno><date when="2012">2012</date><idno type="stanalyst">PASCAL 12-0206474 INIST</idno><idno type="RBID">Pascal:12-0206474</idno><idno type="wicri:Area/PascalFrancis/Corpus">001401</idno><idno type="wicri:Area/PascalFrancis/Curation">004B12</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000F25</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000F25</idno><idno type="wicri:doubleKey">0002-9297:2012:Huppke P:mutations:in:slc</idno><idno type="wicri:Area/Main/Merge">005D60</idno><idno type="wicri:Area/Main/Curation">005A62</idno><idno type="wicri:Area/Main/Exploration">005A62</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin</title><author><name sortKey="Huppke, Peter" sort="Huppke, Peter" uniqKey="Huppke P" first="Peter" last="Huppke">Peter Huppke</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Brendel, Cornelia" sort="Brendel, Cornelia" uniqKey="Brendel C" first="Cornelia" last="Brendel">Cornelia Brendel</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>3 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Christoph Korenke, Georg" sort="Christoph Korenke, Georg" uniqKey="Christoph Korenke G" first="Georg" last="Christoph Korenke">Georg Christoph Korenke</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Neuropediatrics, Children's Hospital</s1><s2>26133 Oldenburg</s2><s3>DEU</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>26133 Oldenburg</wicri:noRegion><wicri:noRegion>Children's Hospital</wicri:noRegion><wicri:noRegion>26133 Oldenburg</wicri:noRegion></affiliation></author><author><name sortKey="Marquardt, Iris" sort="Marquardt, Iris" uniqKey="Marquardt I" first="Iris" last="Marquardt">Iris Marquardt</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Neuropediatrics, Children's Hospital</s1><s2>26133 Oldenburg</s2><s3>DEU</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>26133 Oldenburg</wicri:noRegion><wicri:noRegion>Children's Hospital</wicri:noRegion><wicri:noRegion>26133 Oldenburg</wicri:noRegion></affiliation></author><author><name sortKey="Freisinger, Peter" sort="Freisinger, Peter" uniqKey="Freisinger P" first="Peter" last="Freisinger">Peter Freisinger</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Pediatrics, Klinikum am Steinenberg</s1><s2>72764 Reutlingen</s2><s3>DEU</s3><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>72764 Reutlingen</wicri:noRegion><wicri:noRegion>Klinikum am Steinenberg</wicri:noRegion><wicri:noRegion>72764 Reutlingen</wicri:noRegion></affiliation></author><author><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name><affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Western Sydney Genetics Program, The Children's Hospital at Westmead, and Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney</s1><s2>2145 Westmead</s2><s3>AUS</s3><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><author><name sortKey="Hillebrand, Merle" sort="Hillebrand, Merle" uniqKey="Hillebrand M" first="Merle" last="Hillebrand">Merle Hillebrand</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author><author><name sortKey="Pitelet, Gaele" sort="Pitelet, Gaele" uniqKey="Pitelet G" first="Gaele" last="Pitelet">Gaele Pitelet</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Service de Neuropediatrie, CHU Nice</s1><s2>6200 Nice</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>6200 Nice</wicri:noRegion><wicri:noRegion>CHU Nice</wicri:noRegion><wicri:noRegion>6200 Nice</wicri:noRegion></affiliation></author><author><name sortKey="Wilson, Callum" sort="Wilson, Callum" uniqKey="Wilson C" first="Callum" last="Wilson">Callum Wilson</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>National Metabolic Service, Starship Children's Hospital</s1><s2>1142 Auckland</s2><s3>NZL</s3><sZ>10 aut.</sZ></inist:fA14><country>Nouvelle-Zélande</country><wicri:noRegion>1142 Auckland</wicri:noRegion></affiliation></author><author><name sortKey="Gruber Sedlmayr, Ursula" sort="Gruber Sedlmayr, Ursula" uniqKey="Gruber Sedlmayr U" first="Ursula" last="Gruber-Sedlmayr">Ursula Gruber-Sedlmayr</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Pediatrics, Medical University of Graz</s1><s2>8010 Graz</s2><s3>AUT</s3><sZ>11 aut.</sZ></inist:fA14><country>Autriche</country><wicri:noRegion>8010 Graz</wicri:noRegion></affiliation></author><author><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>3 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Haas, Stefan" sort="Haas, Stefan" uniqKey="Haas S" first="Stefan" last="Haas">Stefan Haas</name><affiliation wicri:level="3"><inist:fA14 i1="09"><s1>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</s1><s2>14195 Berlin</s2><s3>DEU</s3><sZ>13 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Elpeleg, Orly" sort="Elpeleg, Orly" uniqKey="Elpeleg O" first="Orly" last="Elpeleg">Orly Elpeleg</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Monique and Jacques Roboh Department of Genetic Research, Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center</s1><s2>91050 Jerusalem</s2><s3>ISR</s3><sZ>14 aut.</sZ></inist:fA14><country>Israël</country><wicri:noRegion>91050 Jerusalem</wicri:noRegion></affiliation></author><author><name sortKey="Nurnberg, Gudrun" sort="Nurnberg, Gudrun" uniqKey="Nurnberg G" first="Gudrun" last="Nürnberg">Gudrun Nürnberg</name><affiliation wicri:level="3"><inist:fA14 i1="11"><s1>Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne</s1><s2>50931 Cologne</s2><s3>DEU</s3><sZ>15 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Cologne</settlement></placeName></affiliation></author><author><name sortKey="Nurnberg, Peter" sort="Nurnberg, Peter" uniqKey="Nurnberg P" first="Peter" last="Nürnberg">Peter Nürnberg</name><affiliation wicri:level="3"><inist:fA14 i1="11"><s1>Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne</s1><s2>50931 Cologne</s2><s3>DEU</s3><sZ>15 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Cologne</settlement></placeName></affiliation></author><author><name sortKey="Dad, Shzeena" sort="Dad, Shzeena" uniqKey="Dad S" first="Shzeena" last="Dad">Shzeena Dad</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department for Applied Human Molecular Genetics Kennedy Center</s1><s2>2600 Glostrup</s2><s3>DNK</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Danemark</country><wicri:noRegion>Department for Applied Human Molecular Genetics Kennedy Center</wicri:noRegion></affiliation></author><author><name sortKey="Birk M Ller, Lisbeth" sort="Birk M Ller, Lisbeth" uniqKey="Birk M Ller L" first="Lisbeth" last="Birk M Ller">Lisbeth Birk M Ller</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department for Applied Human Molecular Genetics Kennedy Center</s1><s2>2600 Glostrup</s2><s3>DNK</s3><sZ>17 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>Danemark</country><wicri:noRegion>Department for Applied Human Molecular Genetics Kennedy Center</wicri:noRegion></affiliation></author><author><name sortKey="Kaler, Stephen G" sort="Kaler, Stephen G" uniqKey="Kaler S" first="Stephen G." last="Kaler">Stephen G. Kaler</name><affiliation wicri:level="1"><inist:fA14 i1="13"><s1>Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health</s1><s2>Bethesda, MD 20814</s2><s3>USA</s3><sZ>19 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Bethesda, MD 20814</wicri:noRegion></affiliation></author><author><name sortKey="G Rtner, Jutta" sort="G Rtner, Jutta" uniqKey="G Rtner J" first="Jutta" last="G Rtner">Jutta G Rtner</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Pediatrics and Pediatric Neurology, Georg August University</s1><s2>37075 Gottingen</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">American journal of human genetics</title><title level="j" type="abbreviated">Am. j. hum. genet.</title><idno type="ISSN">0002-9297</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of human genetics</title><title level="j" type="abbreviated">Am. j. hum. genet.</title><idno type="ISSN">0002-9297</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autosomal character</term><term>Cataract</term><term>Congenital</term><term>Copper</term><term>Genetic disease</term><term>Genetics</term><term>Hearing loss</term><term>Human</term><term>Low</term><term>Mutation</term><term>Recessive character</term><term>Serum</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Cataracte</term><term>Surdité</term><term>Mutation</term><term>Maladie héréditaire</term><term>Caractère autosomique</term><term>Caractère récessif</term><term>Congénital</term><term>Faible</term><term>Sérum</term><term>Cuivre</term><term>Génétique</term><term>Homme</term><term>Forme fatale</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Cuivre</term><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Autriche</li><li>Danemark</li><li>France</li><li>Israël</li><li>Nouvelle-Zélande</li><li>États-Unis</li></country><region><li>Basse-Saxe</li><li>Berlin</li><li>District de Cologne</li><li>Nouvelle-Galles du Sud</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Berlin</li><li>Cologne</li><li>Göttingen</li><li>Sydney</li></settlement><orgName><li>Université de Sydney</li></orgName></list><tree><country name="Allemagne"><region name="Basse-Saxe"><name sortKey="Huppke, Peter" sort="Huppke, Peter" uniqKey="Huppke P" first="Peter" last="Huppke">Peter Huppke</name></region><name sortKey="Brendel, Cornelia" sort="Brendel, Cornelia" uniqKey="Brendel C" first="Cornelia" last="Brendel">Cornelia Brendel</name><name sortKey="Christoph Korenke, Georg" sort="Christoph Korenke, Georg" uniqKey="Christoph Korenke G" first="Georg" last="Christoph Korenke">Georg Christoph Korenke</name><name sortKey="Freisinger, Peter" sort="Freisinger, Peter" uniqKey="Freisinger P" first="Peter" last="Freisinger">Peter Freisinger</name><name sortKey="G Rtner, Jutta" sort="G Rtner, Jutta" uniqKey="G Rtner J" first="Jutta" last="G Rtner">Jutta G Rtner</name><name sortKey="Haas, Stefan" sort="Haas, Stefan" uniqKey="Haas S" first="Stefan" last="Haas">Stefan Haas</name><name sortKey="Hillebrand, Merle" sort="Hillebrand, Merle" uniqKey="Hillebrand M" first="Merle" last="Hillebrand">Merle Hillebrand</name><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><name sortKey="Marquardt, Iris" sort="Marquardt, Iris" uniqKey="Marquardt I" first="Iris" last="Marquardt">Iris Marquardt</name><name sortKey="Nurnberg, Gudrun" sort="Nurnberg, Gudrun" uniqKey="Nurnberg G" first="Gudrun" last="Nürnberg">Gudrun Nürnberg</name><name sortKey="Nurnberg, Peter" sort="Nurnberg, Peter" uniqKey="Nurnberg P" first="Peter" last="Nürnberg">Peter Nürnberg</name><name sortKey="Ullmann, Reinhard" sort="Ullmann, Reinhard" uniqKey="Ullmann R" first="Reinhard" last="Ullmann">Reinhard Ullmann</name></country><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Christodoulou, John" sort="Christodoulou, John" uniqKey="Christodoulou J" first="John" last="Christodoulou">John Christodoulou</name></region></country><country name="France"><noRegion><name sortKey="Pitelet, Gaele" sort="Pitelet, Gaele" uniqKey="Pitelet G" first="Gaele" last="Pitelet">Gaele Pitelet</name></noRegion></country><country name="Nouvelle-Zélande"><noRegion><name sortKey="Wilson, Callum" sort="Wilson, Callum" uniqKey="Wilson C" first="Callum" last="Wilson">Callum Wilson</name></noRegion></country><country name="Autriche"><noRegion><name sortKey="Gruber Sedlmayr, Ursula" sort="Gruber Sedlmayr, Ursula" uniqKey="Gruber Sedlmayr U" first="Ursula" last="Gruber-Sedlmayr">Ursula Gruber-Sedlmayr</name></noRegion></country><country name="Israël"><noRegion><name sortKey="Elpeleg, Orly" sort="Elpeleg, Orly" uniqKey="Elpeleg O" first="Orly" last="Elpeleg">Orly Elpeleg</name></noRegion></country><country name="Danemark"><noRegion><name sortKey="Dad, Shzeena" sort="Dad, Shzeena" uniqKey="Dad S" first="Shzeena" last="Dad">Shzeena Dad</name></noRegion><name sortKey="Birk M Ller, Lisbeth" sort="Birk M Ller, Lisbeth" uniqKey="Birk M Ller L" first="Lisbeth" last="Birk M Ller">Lisbeth Birk M Ller</name></country><country name="États-Unis"><noRegion><name sortKey="Kaler, Stephen G" sort="Kaler, Stephen G" uniqKey="Kaler S" first="Stephen G." last="Kaler">Stephen G. 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